Cannabinoid (CB1) receptors are the initial site of action for the primary psychoactive ingredient of the most commonly abused street drug, marijuana. In addition, activation of the CB1 receptor augments addictive effects of cocaine and heroin and the development of opioid dependence. The goal of this proposal is to elucidate the functional features of the CB1 receptor that may define mechanisms of drug-receptor interactions relevant to drug, abuse. We have already made progress identifying some of the structural and concomitant functional features of the CB1 receptor molecules. We propose to specifically characterize the regions in the CB1 receptor (motifs) involved in ligand recognition, activation and desensitization. Activation, in the context of this proposal, is the drug-induced alteration of receptor structure that allows interaction with signal transducing G-proteins. Desensitization is a mechanism of modulating the extent of receptor response and may be important in the development of tolerance to the cognate drug. The first aim is to more precisely define the structural features of C1, that lead to differential ligand recognition. The second aim tests the hypothesis that different ligands trigger one of multiple conformational states of the receptor, each of which activate different G protein signaling pathways. As a complementary approach to defining the critical structural features of the receptor, we will correlate naturally occurring mutations (polymorphisms) in the CB1 receptor with specific changes in funtion. Natural mutations of other Gprotein coupled receptors have previously been shown to alter receptor and to cause disease. The third aim tests the hypothesis that specific cannabinoid compounds differentially slesensitize the CB1 receptor response. This may be a mechanism for the production of the distinct pharmacological responses we have observed for these compounds. The consequences of CB1 receptor mutation may be altered neurological functions including predisposition to addiction.